Simultaneous determination and pharmacokinetics study of valsartan, sacubitril and its major metabolite in human plasma, urine and peritoneal dialysis fluid in patients with end-stage renal disease by UPLC-MS/MS.

Sacubitril/valsartan was indicated for the treatment of heart failure and hypertension in patients with end-stage renal disease on peritoneal dialysis therapy. Herein, a rapid, sensitive and robust method based on ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination of the concentrations of valsartan, sacubitril and its major metabolite LBQ657 in plasma, urine and peritoneal dialysis fluid. Samples were extracted from various biological fluids using protein precipitation. Extracts were subjected to UPLC-MS/MS with electrospray ionization in positive-ion mode. The developed method was fully validated over a concentration range of 8.00-8000 ng/mL for valsartan, 2.00-2000 ng/mL for sacubitril and 30.0-30,000 ng/mL for LBQ657 in plasma, 2.00-1000 ng/mL for valsartan, 1.00-500 ng/mL for sacubitril and 20.0-10000 ng/mL for LBQ657 in urine, and 0.200-100 ng/mL for valsartan, 0.0400-20.0 ng/mL for sacubitril and 2.00-1000 ng/mL for LBQ657 in peritoneal dialysis fluid. The intra- and inter-day precisions for all analytes in various matrices were less than 12.3%, and the intra- and inter-day accuracies results were all between 88.0% and 109.2%. All analytes were stable for at least 8 h at room temperature (25°C), five freeze-thaw cycles, and 37 days at -40°C and -80°C in plasma, urine and peritoneal dialysis fluid. In conclusion, this developed method is reliable, sensitive and specific for determining the concentrations of valsartan, sacubitril and LBQ657 in plasma, urine and peritoneal dialysis fluid. The assay was available to pilot the pharmacokinetics study of sacubitril/valsartan in patients with end-stage renal disease on peritoneal dialysis, and it could provide evidence that peritoneal dialysis had an effect on the clearance of sacubitril/valsartan.